Investigational HIV integrase inhibitors in phase I and phase II clinical trials

ABSTRACT

Introduction: To date, three HIV integrase strand transfer inhibitors (INSTIs), i.e. raltegravir, elvitegravir and dolutegravir, have been approved for clinical use. Recent research has focused on new integrase inhibitors including those targeting non-catalytic sites of HIV integrase.

Areas covered: This paper reviews two investigational INSTIs in phase I and II clinical trials, bictegravir (BIC) and cabotegravir (CAB), as well as an investigational noncatalytic integrase inhibitor (NCINI) termed BI 224436.

Expert opinion: Data from phase I and II clinical trials demonstrate that CAB has good efficacy and is well-tolerated. CAB is promising because it can be formulated both orally and as a long-acting (LA) injectable for treatment and prevention of HIV infection. Since LA-CAB formulation offers the possibility of favourable dosing, it may help individuals who struggle with adherence issues. BIC also represents a promising safe, effective and well-tolerated drug that can be administered as a single once-daily regimen in coformulation with emtricitabine and tenofovir alafenamide (FTC/TAF). Ongoing phase III trials should clarify optimal doses and reveal the potential clinical advantages of these new drugs and formulations over other current regimens. Exploration of novel HIV integrase inhibitors acting through mechanisms different from those of INSTIs is still needed.

KEYWORDS:

• BI-224436
• bictegravir
• cabotegravir
• clinical trial
• HIV
• integrase inhibitors

Article highlights

• The emergence of drug resistance and issues of adherence both call for the development of novel anti-HIV agents that are able to overcome resistance and/or simplify regimens.

• HIV integrase inhibitors that block the strand transfer activity of HIV integrase, known as integrase strand transfer inhibitors (INSTIs), have the potential to address these clinical needs.

• Two such new INSTIs are currently in clinical trials: cabotegravir and bictegravir.

• HIV integrase inhibitors that target non-catalytic sites of HIV integrase are also being explored, such as BI 224,436.

• In the future, new HIV integrase inhibitors might be used to simplify regimens and improve resistance profiles, but also strategies aimed at a functional cure.

This box summarizes key points contained in the article.

Acknowledgments

We are grateful to Shalom Spira for editorial assistance with this manuscript.

This manuscript is dedicated to the memory of Dr. Mark A. Wainberg, who tirelessly fought for those affected by HIV.

Declaration of interest

The work conducted in our laboratory is supported by the Canadian Institute of Health research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.